Many microorganisms appear resistant to the effects of inhibitory agents due, at least in part, to the molecular composition of their outer membranes and the selective permeability that these structures provide. Outer envelopes may form an effective barrier to certain macromolecules while at the same time allowing others (such as nutrients) to enter. As might be expected, a great deal of interest has been focused on the structure and function of these microbial membranes and upon a small group of agents which appear to have the ability to alter membrane permeability. It has been the hope that these agents might provide important clues about the molecular nature of selective permeability in microorganisms and about its role in microbial pathogenesis. It has also been the hope that, once past this permeability barrier, antimicrobial agents previously thought to be ineffective might prove to be therapeutically useful. It has been recognized for some time that a variety of naturally occurring, low molecular weight substances bind avidly with the lipopolysaccharide moiety of certain bacteria and, in the process, dramatically disrupt, but sometimes only transiently, outer membrane integrity. This allows access through the outer membrane to their final target, the cytoplasmic membrane, where the primary antimicrobial activity is thought to take place. Melittin, the principle toxic component of honeybee (Apis mellifera) venom, is a 26 amino acid, cationic oligopeptide with strong channel forming activities previously demonstrated in eukaryotic cells, in multilamellar phospholipid vesicles and in Escherichia coli . As we have recently reported, the effect of this molecule upon Borrelia burgdorferi cells growing in culture as monitored by dark field and scanning electron microscopy and by spectrophotometry, is both immediate and profound. At very low melittin concentrations, virtually all spirochete motility ceased within seconds of inhibitor addition. Ultrastructural examination of these spirochetes by scanning electron microscopy revealed obvious alterations in the surface envelope of the spirochetes. However, further study revealed that in contrast to published reports with E. coli, cultures of B. burgdorferi were not sterilized even at extremely high concentrations of melittin. Although some spirochetes were apparently permeabilized quite effectively, others rapidly developed resistance to very high concentrations of the substance over many passages. This has suggested new avenues of research presently underway.